Metabolic engineering of Yarrowia lipolytica for high-level production of scutellarin

Abstract

Scutellarin drugs have been recognized as a key item in the national development of essential clinical emergency drugs for treating cardiovascular and cerebrovascular diseases; therefore, the market demand for scutellarin is growing rapidly. Microbial synthesis based on synthetic biology is a promising method for industrial production of scutellarin. In this study, the highest reported scutellarin titer in the shake flask of 703.01 ± 4.83 mg/L was achieved in Yarrowia lipolytica through the systematic metabolic engineering modifications, including screening for the optimal flavone-6-hydroxylase–cytochrome P450 reductase combination SbF6H–ATR2 to enhance P450 enzyme activity, increasing the copy numbers of rate-limiting enzyme genes, overexpressing ZWF1 and GND1 to increase NADPH supply, enhancing the supply of p-coumaric acid and uridine diphosphate glucose, and introducing the heterologous gene VHb to enhance oxygen supply. This study has significant implications for the industrial production of scutellarin and other valuable flavonoids in green economies.